Bis-hydrazones



' BEST AVAlLABLE COPY BIS-HYDRAZONES Heinrich Jensch, Frankfurt am Main Hochst, Germany, assignor to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius und Briining, Frankfurt am Main Hoehst, Germany, a company of Germany No Drawing. Application September 3, 1952, Serial No. 307,697. In Germany July 24, 1950 6 Claims. (Cl. 260564) 1 The present invention relates to new bis-hydione, hexene (1)-dione(4.5), pentene(1) -dione drazones. (4.5) hexane-2.3-dione, and others. -I' have found that hitherto unknown bis- According to a further feature of the inven- I hydrazones of aliphatic, vioinal dioxo comtion the compounds may be obtained by conpounds can be prepared, which have in one hydensing a monoguanyl-hydrazone of an alldrazone group a guanyl radical and in the other phatic, vicinal di-oxo compound with a phenyl a phenyl radical containing one of the following hydrazine which contains in the phenyl nucleus substituents: one of the three specified substituents.

NH According to a still further feature of the invention it is also possible to condense with amino- C guanidlne a mono-phenyl-hydrazone of an ali- NH: phatic, vicinal di-oxo compound containingin I the nucleus a group which can be transformed into one of the specified substituents, and to -Nll-C transform this group into one of the said substituents. or Suitable aliphatic hydrocarbon radicals having 1 to 3 carbon atoms, which may be used according to the present invention, are, for examc1-I=.\*-.\"n-c pie methyl, ethyl, propyl, isopropyl, allyl, vinyl and others.

The compounds thus obtained are distinguished by their ehicacy in protozoan infections, i. e. for combating babesia and trypano- The products thus obtained have the following structural formula:

E 3 somes. Moreover, the compounds possess bac- A Z tericidal properties. R The following examples serve to illustrate the invention but they are not intended to limit it thereto: wherein R. stands for a member of the group cono mple 1 sisting of 0H; NH

Nn E

NH-N'=CH- =N'NHC HN \\O NH: NH2 ",3

HzN NH v a 65 grams of pyroracemlc aldehyde-para-guanyl-phenyl-hydrazone hydrochloride are mixed mi, in 500 cc. of water with a solution of grams and 0 of amino-guanidine nitrate in 180 cc. of water.

After having been slightly acidified with dilute nitric acid, the mixture is heated, while stirring, -Cl1=N-NH-C\ in the water-bath until a clear solution is obtained. The solution is then mixed with an excess of dilute nitric acid and the yellow magma formed on cooling is filtered with suction and washed with dilute nitric acid. The dinitrate According to one feature of the 1nvent1on the thus obtained, of the Compound corresponding Spemfied compounds are Obtained by condensmg to the formula given above, is then transformed with amino'guanidine mono'phenyl'hydra' into the carbonate by mixing it, while stirring,

and R. stands for a member of the group consisting of hydrogen, methyl; ethyl and allyl.

Zone of an aliphatic, V c di0X0C0mD01lI1d with sodium carbonate solution. The carbonof which the p yl nucl s n ns n o h ate is filtered with suction and washed with icespecified substituents. As aliphatic, vicinal clicold water. After having been dried at ordinary 0x0 compounds there may be named, for example, t mp ature it constitutes an Ochre-yellow D pyroracemic aldheyde, diacetyl, pentane-2.3 der which, on subsequently stirrin with meth-.-

BEST AVAILABLE COPY After having been recrystallised from water, the

dinitrate melts at 276 C. with violent decomposition. The lactate, which is obtained from the carbonate in a manner analogousto that Of. ob:

taining the hydrochloride, melts 211,353" iCl-25efff C., with decomposition.

The starting material, -i. e. the pyroracemic aldehyde-para-guanylphenylehydrazone hydrochloride, is suitably prepared as'roudwsfirhe hydrochloric acid solution of 63 grams of .para:

amino-benzamidine dihydrochloride (melting at 28i C. with decomposition, and obtained from the para-nitro cornp'oundby reduction with hydrogen and a nickel catalystl, which solution has been diazotized with 21 grams of sodium nitrite,

is mixed w-ith an acetoacetic acid solution obby allowing a solution of 40 grams of acetdacetic ester to stand for 24 hours in 670 cc. of

athletic potash sollution of 2.76 per cent. strength and then acidifying'it with 310 cc. of 2 N -hydrochloric acid;. 220cc. of saturated sodium acetate sdlu'tion are graduallyaddedfto the mixture, while stirring, dhring" which operation a thick, brownish-yellowlprecipitate is formed with evolution of carbon dioxidefjtheprecipitate is allowed to stand for 's'everahhoursl:filtered'with suction and Example 2 PIN. cm NH l c NHN=C H-C=N-NH-C HzN NHa.

27 grams of pyroracemic aldehyde-metaguanyl-phenyl-hydrazbne" nitrate are acidified with a small quantity of dilute nitric acid and then mixed in 200 cc. of water with a solution of 14 grams of amino-guanidine nitrate. The mixture is heated for 1 hour in a water bath, while stirring; after cooling, an excess of dilute nitric acid is added and the di-nitrate corresponding to'the above formula is filtered with suction and washed withN-nitric acid and acetone. It constitutes a brown-red powder which readily dissolves in hot water; it is moderately soluble in cold.'water, and after it has been recrystallised from water it melts at 262 C. with decomposition. The carbonate, obtained therefrom as described in Example 1, constitutes a grey-yellow powder which is dried under reduced pressure and then transformed, in the same manner as the paracompound, into the di-hydrochloride. A brownish-red crystalline powder is obtained which, after recrystallisation from methanol and acetone, melts at 273 C. with decomposition; it is readily soluble in water, methanol and dilute hydrochloric acid and sparingly soluble in ethanol. The pyroracemic aldehyde-meta-guanyl phen yl-hydrazone is prepared in a manner analogous to that of the para-compound, using metaamino-benzamidine dihydrochloride (see Berichte der Deutschen Chemischen Gesellschaft, vol. 28, page 486) it is precipitated as the nitrate by mixing the solution oi its hydrochloride with dilute nitric acid. The nitrate constitutes a light red to brown powder which, recrystallised from water, melts at 209 C.-210 C. with decomposition.

25 grams of diacetyl mono para guanylphenyl-hydra'zone hydrochloride in 150 cc. of waterare mixed with a hot solution of 14 grams of aminoguanidine nitrate in 65 cc. of water, whereupon, the mixture. is heatedina water-hat while stirring, until'dissolutio'n has taken place. Oncooling, a practically. colorless..magma ,is formed which is. stirred with an, excess of sodium carbonatesolution, during which. operation it is. transformed. into. the voluminous carbonate which is' centrifuged and washed several'tiines with water. After drying, the carbonate is mixed with methanol, while stirring; by acidifying the mixture with methanolichydrochloric acid, it is transformed into the dihydrochloride which is filtered with suction and'washed with acetone. It constitutes a yellowish powder which readily dissolves in water, forming a reddish-yellow solution. By means of dilute. caustic soda solution the practically colorless crystalline base of the above constitution is precipitated from the solution. After recrystallisation from aqueous methanol, the base melts at 240 C. with decomposition.

The starting material can be obtained according to the method described in Example 1, in the form oi the hydrochloride, by coupling diazotized para amino benzamidine with methyl acetoacetic acid. The hydrochloride constitutes a feebly reddishpowder which is sparingly soluble in cold water and readily soluble 'in hot water. When recrystallised from water, it melts at 272 C. with decomposition; the base precipitated with dilute caustic ,soda solution melts at .19,9C;-2 00f C. with decomposition. Example 4 CH; cm

24.6 grams of diacetyl mono meta guanylphenyl-hydrazone hydrochloride are heated in HN NH NHi the water-bath together with 50 cc. of water anda solution of 15 grams of amino-guanidine carbonate in about 70 cc. of 2 N-hydrochloric acid until complete dissolution has taken place. After cooling, the solution is mixed with concentrated hydrochloric acid and the salt which has, separated, isT filteredwithsuction in the ice-cold conditi and washed with ice-cold dilute hydrochloricacid andacetone, The di-hydrochloride. oi the abovebas'e constitutes an almost colorless.

inc'ompact, powder fwhich readily dissolves in waterf on heating, and forms a' yellow solution. When recrystallised from methanol and acetone, it melts at 302 C. with decomposition.

The starting material is'obtained as described BEST AVAILABLE COPY in Example 3, using meta-amino-benzamidine. It constitutes practically colorless, fine, long small needles and melts at 268 C.-270 C. with decomposition.

. 20.5 grams of pentane-2.3-dione- 3 -paraguanyl phenyl hydrazone hydrochloride are weakly acidified and then heated on the waterbath, while stirring, together with 100 cc. of water and a solution of 9.8 grams of aminoguanidine nitrate in 45 cc. of water, until a clear solution is formed. After cooling in ice, the fine crystalline precipitate is filtered with suction and stirred with an excess of sodium carbonate solution. The carbonate is formed during this operation in the form of a precipitate of the nature of a thick oil which, on cooling and rubbing, becomes crystalline. After drying, the carbonate in methanol is acidified with methanolic hydrochloric acid, during which operation a pale yellow magma of the dihydrochloride of the compond having the formula given above, is formed.

The compound dissolves in Water and forms a red-yellow solution; when recrystallised from a large quantity of methanol, it melts at 244 C. with decomposition.

The starting material is obtained as described in Example 3, using ethyl-acetoacetic acid. It constitutes a reddish crystalline powder which dissolves in hot water and forms a red-yellow solution. The base is precipitated by means of dilute caustic soda solution. When the base has been recrystallised from water and a small quantity of methanol, it constitutes a colorless, fine crystalline powder which, on drying on the Waterbath, assumes a brown color. It melts at 113 C.-1l4 C. With decomposition.

grams of hexane-(1)dione-(4.5)-4-paraguanyl-phenyl-hydrazone hydrochloride in 130 cc. of water are weakly acidified with dilute hydrochloric acid and then heated on the waterbath for about 4 hour with a solution of 9.3 grams of amino-guanidine nitrate in cc. of water. After cooling, the carbonate is precipitated with potassium carbonate solution. After having been washed with water, it constitutes a light yellow powder which is covered by pouring methanol upon it and, on acidifying with methanolic hydrochloric acid, it is transformed, with evolution of carbon dioxide, into the yellow dihydrochloride of the base named above. When recrystallised from methanol and acetone, it melts at 230 C. with decomposition.

The starting material is obtained in a manner analogous to that described in Example 3 by using, instead of methyl, the allyl-acetoacctic acid which is formed in a manner analogous to the process described in Example 1, by shaking the ester for several days with caustic potash solu tion. A feebly reddish, fine crystalline powder is formed. The base may be precipitated from the from water in the form of small brown needles melting at 66-67 C.

Example 7 011; NH NH-N=CH-( =N-NH-C HN C-NH HzN 38 grams of pyroracemic aldehyde-paraguanidinophenyl-hydrazone hydrochloride in cc. of water are heated on the water-bath together with a solution of 25 grams of aminoguanidine carbonate in about cc. of 2 N hydrochloric acid. After the addition of hydrochloric acid in excess and cooling in ice, the dihydrochloride of the above compound is filtered with suction and 'washed with 2 N-hydrochloric acid and acetone. It is purified by dissolving it in water, filtering the solution and reprecipitating with hydrochloric acid in excess. A substantially colorless powder is obtained after recrystallisation from methanol and a small quantity of water with subsequent addition of acetone. The powder melts at 275 C.276 C. with decomposition.

The starting material is obtained by the process described in Example 1, using para-amino-phenyl-guanidine instead of para-amino-benzamidine. A weak reddish, crystalline powder is formed which, after recrystallisation from water, melts at 278 C. with decomposition. Para-aminophenyl-guanidine may be obtained in the form of the carbonate (when recrystallised from water, melting at 180-181 C. with decomposition) by precipitating with saturated potash solution in excess either the catalytically reduced nitrocompound or the para-acetamino-phenyl-guanidine (obtained from para-amino-acetanilide and cyanamide, the carbonate when recrystallised from water melting at 220 C. with decomposition) saponified with dilute hydrochloric acid.

14 grams of pyroracemic aldehyde-para-(guanyl hydrazone formyl) phenyl hydrazone hydrochloride are heated on the water-bath together with 70 cc. of water and a solution of 7.5 grams of aminoguanidine carbonate in about 35 cc. of 2 N-hydrochloric acid until dissolution is complete, whereupon the solution is mixed with hydrochloric acid in excess and the dihydrochloride of the compound of the formula given above is well cooled, filtered with suction and washed with ice-cold dilute hydrochloric acid and acctone. It constitutes a red-brown powder which readily dissolves in water and forms a red solution. The powder is recrystallised from methanol and acetone; it then constitutes a brown crystalline powder melting at 266 C. with decomposition. The nitrate when recrystallised from BEST AVAILABLE COPY sesame 7. water melts :at 2'50. 321-251 'fizvvith decomposition. r Thestarting:materialzmay he preparedinthe manner: described. in; Example: 1- fromv paraa-minoahenzalguanyl-hydrazone and; acetoacetic acid; and :when recrystallised, from-water; it. constitutes .a. brown-red powder melting at 120 0.

with -.decomposition. The paraamino benzal-- guanyl-hydrazone unay. lie-obtained as carbonate in .the :form of a, yellow powder. by precipitatingwith potassium carbonate solution-paramcetamino-benzalguanyl hydrazone. (when recrystallised from water, melting at 238 C. with decomposition) which has been saponified with dilute hydrochloric acid. The powder thus obtained 18 grams of pyroracemic aldehyde-metar (guanylhydrazone formyl) phenyl hydrazone hydrochloride are heated on the water-bath, while stirring, together with 80 cc. of water and a feebly acid solution of grams of amino-guanidine carbonate in about 50 cc. of 2 N-hydrochloric acid. A dark-red solution'is obtained within about hour. a light-brown magma of the dihydrochloride of the abovebase is formed which is cooled in ice, filtered; with suction, and washed with dilute hydrochloric acid and acetone. A reddish-grey powder is obtained which on dissolving in water forms a red solution. It may be recrystallised from alcohol and'acetone and melts at 149 C.- 150" C. with slow decomposition accompanied by swelling.

The starting material may be prepared as described in Example 8, using meta-aminobenzalguanylhydrazone (obtained from the nitro-compound by catalytic reduction; the dihydrochloride melts at 275 C; with decomposition). When recrystallised from water, it constitutes a feebly brownish powder which assumes a black-vio1et coloration by the addition of concentrated hydrochloric acid. The powder melts, at .222 C. with decomposition.

A diazonium hydrochloride solution of paraamino-benzarnidine is reduced at a temperature between 10 C. and 5 C. with a strong stannous chloride solution in hydrochloric acid, the reduction product is neutralised with caustic soda solutiongthe solution is detinned and evaporated to dryness under reduced pressure, the residue is extracted with alcohol and the alcoholic extract is mixed'with ether. The dihydrochloride of the para-hydrazine.- benzamidine is thus obtained which is recrystallised fromalcoholand then melts; at 211 C.-212 C. with decomposition. A solution of 3 grams of this salt is mixed with a hot aqueous solution of 1.75 grams of diacetyl monoguanyl-hydrazone and the mixture is acidified with dilute hydrochloric acid.- After some timedilute hydrochloric acid is added in excess, after cooling in ice the-precipitate is filtered with suction and washed with ice-cold dilute hydro- On addition of hydrochloric acid in excess,

chloriczacid tandacetonei The'fpale yellow 'powder is soluble in wate'r -and for-ms a yellowsolution; The nearly r'colorlessbase; the diacetyl- (guanyl) (para guanyl phenyl) bis-hydra zone, is precipitated from. the solution by means of dilute caustic soda solution. The base melts at 240-241 C. with decomposition. The mixture with the baseoiExample 3&has the same melting point.

The diacetyl-monoguanyl-hydrazone (when recrystallised from water, melting at 214 C..with violent decomposition) may be obtained by careful reaction of 'diacetyl'with the hydrochloride of amino-guanidine.

Example 11;.

.Eyroracemic;aldehyde-para formyl-phenyl hydrazone may be obtained by coupling diazotized para-aminoehenzaldehyde with acetoaoetic acid. When recrystallised irom benzene, the compound constitutes a feebly reddish powder melting at 3 grams .ot the hydrazone thus obtainedv 152 C- are dissolvedin methanol; the solution'is mixed with av hot aqueous solution of 4.5 grams of amino-guanidine nitrateand, after-the addition" ofa small quantity of dilute-nitric acid; the mix- Example 1 2 C HN- 10.15 grams of pyroracemic aldehyde-metaguanidino-phenylhydrazone-nitrate are heated for 1 hour in a water-bath together with a solution of 5 grams of aminoguanidine-nitrate in 100 cc.- of water having been acidified with dilute hydrochloric acid. The solution produced separates, on cooling, the dinitrate of the abovenamed base which is filtered with suction and then washed first with water and then with ace- It may be recrystallized from aqueous tone.- methanol, with-a subsequent addition of acetone, and then forms a fine, crystalline, reddish-gray powder which sparingly dissolves in cold water, butreadilydissolves inhot water. The product melts zit-284 CL, with decomposition. The base dissolves insodium hydroxide'solution used in excess.

The starting material may be prepared 'as follows: IZ-grams of meta-acetaminophenyl-guanidine-carbonate (obtained from the hydrochloride of meta amino acetanilide and cyanamide by precipitation with potassium carbonate solution;

after the recrystallization from water, the nitrate meltsat 205 C., withdecomposition) are heated for 1 hour-in a water-bath together with cc.

of-water and 2000. of concentrated hydrochloric acid. The hydrochloride ofmeta-aminophenyl- BEST AVAILABLE COPi guanidine which is formed during this heating operation is diazotized with 3.5 grams of sodium nitrite and the diazonium solution is mixed with an acetoacetic acid solution obtained by saponification of 7.5 grams of acetoacetic ester with 3.5 grams of caustic potash in 125 cc. of water and a subsequent acidification with 60 cc. of 2 -nhydroch1oric acid. After the addition of saturated sodium acetate solution to the mixture until a reaction to mineral acid can no longer be detected, a red coloration sets in with evolution of carbon dioxide and, after the addition of dilute nitric acid in excess, the pyroracemic aldehyde meta guanidino phenyl hydrazonenitrate separates and is filtered with suction and then washed with very dilute nitric acid and acetone. After the recrystallisation from methanol and acetone, the product melts at 218 C. with decomposition. It constitutes a feebly reddish, crystalline powder.

Example 13 CH: CH: NH

NH-N: -C=N-NH-C HN NH: /C'HN HaN '7 grams of diacetyl-para-guanidino-phenylhydrazone-hydrochloride are heated, while stirring, for 1-2 hours in a water-bath together with 3.6 grams of aminoguanidine -nitrate in about 150 cc. of water, after the addition of a small quantity of dilute hydrochloric acid. Dilute nitric acid in excess is then added and after cooling the product is filtered with suction and washed with very dilute nitric acid and with acetone. The dinitrate of the above base is thus obtained in the form of a pale yellow powder which rather readily dissolves in hot water to form a yellow solution, but which is hardly soluble in cold water. On stirring with hot sodium hydroxide solution, the base is formed which. when recrystallized, still in the moist state, from methanol, constitutes, after drying, a goldenyellow powder. The product melts at 180 C. with decomposition. It is readily soluble in dilute acetic acid; with dilute hydrochloric acid in excess it forms the crystalline, colorless dihydrochloride.

The starting material is obtained by the addition of saturated sodium acetate solution to the mixture of a diazonium hydrochloride solution of para-aminophenyl-guanidine with a methylacetoacetic acid solution in the form of a solid, colorless hydrochloride. When recrystallized from aqueous methanol with th subsequent addition of acetone, the product melts at 300 C. with decomposition.

Example 14 EN CH; CH: NH \C-HN-N=HC Nun-(t at: -NH-C// HSN/ NH:

16 grams of di-acetyl-meta-(guanylhydrazoneformyl)-phenylhydrazone-hydrochloride and 7.5 grams of aminoguanidine-nitrate are heated in the Water-bath in '75 cc. of water which has been acidified with dilute hydrochloric acid, during which operation a very dark-red solution is gradually formed. While the solution is still hot, it is mixed with dilute nitric acid in excess. After cooling, the dinitrate of the above-named base which has separated is filtered with suction and washed with n/l-nitric acid and acetone. It constitutes a reddish-gray powder which readily dissolves in hot water to form a red solution. When cooled, the solution assumes a jelly-like consistency. On heating with dilute sodium hydroxide solution, the base is formed. After recrystallization from methanol and water, a feebly reddish powder is obtained which melts at 238 C. with decomposition. The powder readily dissolves in dilute acetic acid to form a reddish solution; a jelly-like hydrochloride is precipitated from the solution by means of hydrochloric acid applied in excess.

The starting material is obtained in the form of the hydrochloride, as it is described in Example 9, while using methyl-acetoacetic acid as a feebly reddish powder, which, when recrystallized from methanol and ether, melts at 242 C. to 243 C. with decomposition.

This application is a continuation-impart of application Serial No. 237,061 filed July 16, 1951.

I claim:

1. The compounds of the following general formula wherein R stands for a member selected from the group consistmg of hydrogen and aliphatic hydrocarbon radicals containing 1 to 3 carbon atoms.

2. The compounds of the general formula om /Nil us Nn-N on-o n-Nu-o C-HNN=H NH HEN 3. The compounds of the general formula CH3 on: /Nl1 HN NH-N- N-NHC C-HNN=HC NH! HzN 4. The compound of the formula OH; NH

I NH-N=CH-C=N-NH-C HN N112 /C-HN-N=HC H2N 5. The compound of the formula HN\ OH: //NH \C-HN-N=HC NH-N=CH-(5=N-NH-C\ HzN NH:

6. The compound of the formula: HN\ CH; OH; //NH \O-HN-N=HC NH-N: -(g=N-NH-C HaN NH:

HEINRICH J ENSCH.

No references cited. 

1. THE COMPOUND OF THE FOLLOWING GENERAL FORMULA 